Homozygosity for the V37I <i>GJB</i><i>2</i> mutation in fifteen probands with mild to moderate sensorineural hearing impairment: Further confirmation of pathogenicity and haplotype analysis in Asian populations

Gallant, Emily; Francey, Lauren J.; Tsai, Ellen; Berman, Micah A.; Zhao, Yaru; Fetting, Heather; Kaur, Maninder; Deardorff, Matthew A.; Wilkens, Alisha; Clark, Dinah; Hákonarson, Hákon; Rehm, Heidi L.; Krantz, Ian D.

doi:10.1002/ajmg.a.36042

Cited by 19 publications

(15 citation statements)

References 30 publications

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“…Some studies indicated that the p.Val37Ile and p.Met34Thr missense variants were benign polymorphisms [ 3 , 23 ]. Results of other studies supported their pathogenicity and implicated their association with a mild-to-moderate hearing impairment [ 1 , 24 , 25 ]. We detected one compound c.35delG and p.Val37Ile heterozygous individual with a severe prelingual hearing disorder.…”

Section: Discussionmentioning

confidence: 56%

Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia

et al. 2018

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Background and Objective: Hearing loss is the most common sensory deficit in humans. The aim of this study was to clarify the genetic aetiology of nonsyndromic hearing loss in the Moravian-Silesian population of the Czech Republic. Patients and Methods: This study included 200 patients (93 males, 107 females, mean age 16.9 years, ranging from 4 months to 62 years) with nonsyndromic sensorineural hearing loss. We screened all patients for mutations in GJB2 and the large deletion del(GJB6-D13S1830). We performed further screening for additional genes (SERPINB6, TMIE, COCH, ESPN, ACTG1, KCNQ4, and GJB3) with Sanger sequencing on a subset of patients that were negative for GJB2 mutations. Results: We detected biallelic GJB2 mutations in 44 patients (22%). Among these patients, 63.6%, 9.1% and 2.3% exhibited homozygous c.35delG, p.Trp24*, and p.Met34Thr mutations, respectively. The remaining 25% of these patients exhibited compound heterozygous c.35delG, c.-23+1G>A, p.Trp24*, p.Val37Ile, p.Met34Thr, p.Leu90Pro, c.235delC, c.313_326del14, p.Ser139Asn, and p.Gly147Leu mutations. We found a monoallelic GJB2 mutation in 12 patients (6.6%). We found no pathogenic mutations in the other tested genes. Conclusions: One fifth of our cohort had deafness related to GJB2 mutations. The del(GJB6-D13S1830), SERPINB6, TMIE, COCH, ESPN, ACTG1, GJB3, and KCNQ4 mutations were infrequently associated with deafness in the Moravian-Silesian population. Therefore, we suggest that del(GJB6-D13S1830) testing should be performed only when patients with deafness carry the monoallelic GJB2 mutation.

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Section: Discussionmentioning

confidence: 56%

Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia

et al. 2018

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“…[ 37 ] At present, the pathogenicity of this mutation site is controversial, because some individuals with normal hearing also carry the homozygous mutation. [ 38 , 39 ]…”

Section: Discussionmentioning

confidence: 99%

Analysis of mutation spectrum of common deafness-causing genes in Hakka newborns in southern China by semiconductor sequencing

2018

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Hearing loss is a common neurosensory disorder, approximately half of the cases are caused by genetic factors, and approximately 70% of hereditary hearing impairments are nonsyndromic hearing loss (NSHL). The mutations of GJB2 (gap junction beta-2 protein), GJB3 (gap junction beta-3 protein), SLC26A4 (solute carrier family 26 member 4), and MT-RNR1 (mitochondrially encoded 12S RNA) are the most common inherited causes of NSHL. Because of different genetic backgrounds, the mutation spectrum of these common deafness-causing genes varies among different regions in China. Because no data are known on these mutations among the Hakka population of Southern China, we aim to investigate the mutation spectrum to add these to neonatal screening and genetic counseling. A total of 1252 blood samples from newborns have been detected by semiconductor sequencing for 100 mutations loci of 18 deafness-causing genes. Of the participants, 95 subjects carried deafness-causing genes mutations with the carrier rate of 7.59%. The mutation frequencies of GJB2, SLC26A4, GJB3, and mitochondrial genes were 3.04%, 3.51%, 0.16%, and 0.88%, respectively. We followed up subjects with single-gene homozygous or compound heterozygous mutations. Our study firstly analyzed deafness-causing genes mutation spectrum in Hakka population, providing evidence for future neonatal screening and genetic counseling in this area.

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“…These findings confirm our earlier reported data on the high prevalence of the c.-23+1G>A pathogenic variant among the Yakut population in Eastern Siberia [ 84 ]. Interestingly, in the Yakut patients, the second most common pathogenic variant was c.109G>A (p.Val37Ile), which was found with high frequency in Southeast Asia (Thailand, Indonesia, Malaysia) [ 41 , 47 , 48 ], East Asia (China, Korea, Japan) [ 33 , 35 – 38 , 40 , 42 , 44 , 46 ], and Australia [ 71 ], as well as among patients with HI of Asian origin in the US [ 87 ]. Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were the most frequent in the group of Russian patients.…”

Section: Discussionmentioning

confidence: 99%

Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic)

et al. 2016

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Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts—296, Russians—51, mixed and other ethnicities—46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c.-23+1G>A and с.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of с.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate.

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Homozygosity for the V37I GJB2 mutation in fifteen probands with mild to moderate sensorineural hearing impairment: Further confirmation of pathogenicity and haplotype analysis in Asian populations

Cited by 19 publications

References 30 publications

Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia

Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia

Analysis of mutation spectrum of common deafness-causing genes in Hakka newborns in southern China by semiconductor sequencing

Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic)

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